1. Field of the Invention
The present invention relates to methods for using recombinant Herpes simplex virus to treat neuronal degeneration. More particularly, this invention relates to methods for treating neuronal degeneration, including ocular neuronal degeneration, by administering a Herpes simplex virus that expresses a therapeutic gene in infected cells, but does not express ribonucleotide reductase.
2. Related Art
Degenerative diseases of the retina are a leading cause of vision loss in the United States, affecting approximately two million people each year. VISION RESEARCH--A NATIONAL PLAN, 1994-1988, Report of the National Advisory Eye Council, National Institutes of Health, National Eye Institute, pages 41 and 55; Berson, Proc. Nat'l Acad. Sci. USA 93:4526 (1996). Certain retinal degenerations, such as retinitis pigmentosa are clearly inherited and can be classified as autosomal dominant, autosomal recessive, or X-linked. Humphries et al., Science 256:804 (1992).
Another major cause of retinal degeneration is macular degeneration. Macular degeneration primarily affects people older than 65 and is a leading cause of blindness in this group. The majority of macular degeneration has not yet been linked to genetic factors and the cause of macular degeneration remains unknown for most patients. VISION RESEARCH--A NATIONAL PLAN, 1994-1988, Report of the National Advisory Eye Council, National Institutes of Health, National Eye Institute, pages 41 and 55.
Recent studies on retinitis pigmentosa have shown that mutations in several genes coding for proteins in the phototransduction pathway are involved. Most are in rhodopsin but the peripherin/rds (retinal degeneration slow) gene, cyclic GMP-phosphodiesterase gene, and the RCC1 guanine nucleotide exchange factor may also be involved. See, for example, Dryja et al., Proc. Nat'l Acad. Sci. USA. 88:6481 (1991); Inglehearn et al., Hum. Mol. Gen. 1:41-45 (1992); Al-Maghtheh et al., Hum. Mol. Gen. 3:205 (1994); Meindl et al., Nature Genetics 13:35 (1996). In humans, retinitis pigmentosa has been mapped to other genetic loci indicating that several other genes may be involved in the disease. Humphries et al., Science 256:804 (1992). Recent results have also identified a mutation in the human peripherin/rds gene in the cause of autosomal dominant macular dystrophy in three families. McLaughlin et al., Nature Genetics 4:130 (1993); Gal et al., Nature Genetics 7:64 (1995). These results suggest that both retinitis pigmentosa and macular degeneration may have a common underlying mechanism, defects in phototransduction proteins, and that common strategies for treatment might be possible. Mutations in the rod C-GMP phosphodiesterase .beta.-2 subunit gene have been implicated in autosomal dominant stationary night blindness, again suggesting that defects in phototransduction cascade proteins cause several retinal degenerative diseases. Tsang et al., Science 272:1026 (1996).
Gene therapy is certainly one strategy that might be used for treatment in individuals where the defective gene has been identified. Several factors, however, suggest that the replacement of a specific gene in a patient might not be effective. A clinical test to determine the mutation would be required. This is not yet widely available and would likely require that specialized diagnostic centers be established. Moreover, a method for the delivery of the gene to the photoreceptor cells is needed. Finally, many of the conditions are autosomal dominant, and placing a normal copy of the gene into the cells would not correct the defect. Treatment would have to "turn off" the mutant allele, which would be very difficult to do in all cells.
Recent studies of the effects of neurotrophins (i.e., growth factors for nerves) have provided information that may be used to develop a gene therapy treatment for several retinal degenerations which would not require the identification of the mutation. For example, injection of bFGF or brain derived neurotrophic factor (BDNF) into the vitreous delays retinal degeneration and light-induced retinal degeneration in albino rats. LaVail et al., Proc. Nat'l Acad. Sci. USA 89:11249 (1992); Faktorovich et al., Nature 347:83 (1990). The effect, however, is transient and continued administration of the factor is required for long term preservation. If genes for these factors could be delivered to the eye, continued synthesis should be therapeutically useful.
Therefore, a need exists for a means to deliver therapeutic polypeptides or proteins on a continuous basis to treat neuronal degeneration.